A multiscale study of dynamic gap junctions in myocyte-fibroblast interactions

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 DESCRIPTION (provided by applicant): The adult heart is composed of a dense network of cardiomyocytes surrounded by non-myocyte cells, the most abundant of which are cardiac fibroblasts. Several cardiac diseases, such as myocardial infarction or dilated cardiomyopathy, are associated with an increased density of fibroblasts (fibrosis). Fibroblasts are known to play a significant role in the development of electric and mechanical dysfunction of the heart, however the exact mechanisms are poorly understood. One emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junctional channels (GJCs). Recent in vitro studies have demonstrated that fibroblasts can induce spontaneous electrical activity, modify conduction velocity, and reduce action potential duration of cardiomyocytes through direct electrical coupling via GJCs. GJCs are intercellular channels that provide a direct pathway for communication between neighboring cells. In the heart, three major connexin (Cx) isoforms, Cx40, Cx43 and Cx45 form GJCs in cell-type-specific combinations. Because each Cx is characterized by unique dynamic properties (i.e., voltage-dependent conductance profile), I hypothesize that the electrophysiological contributions of fibroblasts will vary with the specific composition of the myocyte-fibroblast GJC. Understanding such electrophysiological contributions, and their variation as a function of cardiac tissue type, is especially important in the context of the enhanced arrhythmogenic state accompanying diseased states with increased fibrosis. To investigate the role of dynamic GJC properties in myocyte-fibroblast interactions, the proposed study will use a multi-scale experimental and computational modeling approach. First, a mathematical model of the dynamic properties of the myocyte-fibroblast GJCs will be developed. Then, using the dynamic-clamp technique and computer simulations, these models will be used to investigate the effects of the dynamic GJC phenotype on the electrophysiological contribution of fibroblasts on the cardiomyocyte action potential (AP) duration and morphology. Changes in AP duration and morphology are key factors in the development of cardiac arrhythmia. Moreover, the proposed study will use a new approach to quantify intercellular GJC communication between myocytes and fibroblast in cardiac tissue. This will be important step towards under- standing the implications of myocyte-fibroblast interactions in the whole heart. Finally, the findings of the dynamic clamp studies and the intercellular communication studies will be incorporated into a detailed two-dimensional computational model of normal and heart failure tissue with patchy fibrosis. This will allow for an investigation of how dynamic GJCs modify fibroblast-mediated changes in conduction velocity and vulnerability to reentry during cardiac fibrosis. Such a multi-scale computational and experimental investigation of myocyte-fibroblast interactions will provide mechanistic insight into which processes play a key role in modifying the cardiomyocyte electrophysiology during cardiac fibrosis.